Page 627 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 28 Tumors of the Mammary Gland 605

significant benefit after 4 years of age. According to Schneider’s some found underexpression of BRCA1 in malignant tumors
original study, the risk increases and the benefit diminishes with and others have documented overexpression of BRCA2 in meta-
Germline polymorphisms in both BRCA1 and
35,36
each estrus cycle, as illustrated by an increasing risk of 8% and
static tumors.
VetBooks.ir 26% depending on whether the OHE was performed before BRCA2 were associated with significantly increased risk in English
springer spaniels in a large Swedish study.
3,17
the second or third heat cycle. No significant risk reduction
18

was seen in dogs spayed after 2.5 years of age, although other
researchers have found some modest benefit in dogs spayed later. Other Risk Factors
These studies were all retrospective case-control studies. 14,19,20 Body weight, specifically during puberty (9–12 months), is found
A recent prospective randomized study, however, documented to have a significant effect on later MGT risk; being underweight
significant decreased risk for new tumor development by per- during this time period provides significant protection against later
forming OHE concurrent with tumor removal in dogs with tumor development. This study did not find an increased risk for
19
benign MGTs. Notably, these dogs were older, with a mean tumors in dogs fed a high-fat diet or dogs that were obese around
21
age of 9 years, confirming that hormonal deprivation via OHE the time of tumor detection; however, a subsequent case-control
later in life significantly decreases the risk for new tumor devel- study did document an association between diet and mammary
opment. Nevertheless, the greatest benefit on MGT prevention cancer in which obesity early in life and a diet high in red meat
is seen if the dog is not allowed to go through any heat cycles, were found to increase risk. Obesity has also been recognized as
37
suggesting that some of the initial effects of ovarian hormones a risk factor for developing postmenopausal BC in women. 38,39
on the MGs in terms of cancer risk occur early in life, likely One of the proposed mechanisms by which diet/obesity may be
during puberty when the MG develops and matures. Other fac- linked to breast carcinogenesis is via its effect on serum estrogen
tors resulting in physiologic variation in hormonal influence on levels. Obesity is associated with decreased concentration of sex
the mammary tissues, such as pseudopregnancy, pregnancy, or hormone–binding globulin and thus results in elevated serum free
parity, which typically occur after a few estrus cycles, have not estrogen levels. 40–44 In addition, adipose tissues may be a source
been found to significantly influence the tumor risk, but none of increased estrogen production via aromatase-mediated conver-
of these studies were controlled or randomized. 14,18,22 Expo- sion of androgens. Interestingly, the mammary cancer–sparing
sure to exogenous or pharmacologic doses of hormones (both influence of being underweight is most significant during the first
progestins and estrogens) has been found to increase the risk year of life, when the effects of the endogenous hormones are the
for developing MGTs in dogs. Dogs treated with progestins are greatest.
20
more likely to develop tumors and at a younger age. Accord-
ing to the Norwegian Canine Cancer Registry, dogs treated with Tumor Biology: Development, Hormones,
progestins to prevent estrus had a 2.3-fold higher risk for MGTs
compared with dogs not receiving such treatment. Similarly, a Growth Factors, and Clinical Implications
23
Dutch study found that privately owned dogs with MGTs were Based on the previous discussion of risk factors, it is clear that
20
significantly more likely to have received progestins. Numer- exposure to ovarian hormones is important in the development
ous studies have investigated the effect of dose, duration, and of MGTs in dogs. Both estrogens and progesterone are necessary
type of hormones (progestins, estrogens, or a combination of for normal MG development and maturation. The MGs undergo
both) on MGT development in laboratory dogs. Although some distinct clinical and histopathologic changes as hormone levels
discordance exists, most conclude that low-dose progestins alone fluctuate according to the phases of the estrus cycle. 45,46 Estrogens
increase the risk for predominantly benign tumors, whereas a and progesterone are mitogens of breast epithelium and induce
combination of estrogens and progestins tends to induce malig- proliferation of intralobular ductal epithelium and development
nant tumors. 24–28 of ducts and lobules, resulting in expansion of the MGs. His-
torically, the tumorigenic effects of estrogen in human BC were
Breeds and Genetic Susceptibility thought to be mediated via their receptor binding and enhanced
In general, MGTs tend to be more common in the smaller breeds. production of growth factors resulting in increased cellular pro-
1
47
Purebred dogs are more commonly affected ; poodles, Chihua- liferation ; however, more recent research shows that estrogen
huas, dachshunds, Yorkshire terriers, Maltese, and cocker span- and its metabolites also have direct genotoxic effects by increas-
iels are frequently listed as high-risk breeds in the small-breed ing mutations and induction of aneuploidy independent of the
category. 1,2,16,29 However, some of the larger breeds are also at estrogen receptors. 48–50 The tumorigenic effects of progesterone
increased risk, including the English springer spaniel, English set- are in part thought to be mediated via a progesterone-induced
ters, Brittany spaniels, German shepherds, pointers, Doberman increased MG production of growth hormone (GH) and GH
pinschers, and boxers. 1–3,16,29 Some noteworthy discrepancies receptors. 51–53 GH has direct stimulatory effects on mammary tis-
exist, specifically between the US and European reports. Boxers sues and indirect effects via increasing insulin-like growth factor-1
54
are noted to have a decreased risk for MGTs according to data (IGF-1). The GH/IGF-1 axis has been implicated in human
from the University of Pennsylvania, whereas Scandinavian stud- breast carcinogenesis. IGF-1 is both a proproliferative and a sur-
ies reflect an increased risk in boxers. 2,3,16 A closed population vival factor for breast epithelial cells and regulates the expression
beagle study showed that two different lines or families of beagles of numerous genes involved in BC development. 55–60 The com-
have very different MGT risks. These results collectively support plex dysregulation of growth factors and hormones that precedes,
30
a genetic influence on MGT development. Familial or inherited initiates, and potentially drives canine mammary tumorigenesis is
germline mutations in BRCA1 and BRCA2 account for 5% to far from understood; evidence exists indicating that both growth
10% of all human breast cancers (BCs) and are associated with an factors and steroid hormones are intrinsically implicated and con-
85% cumulative lifetime risk of BC in affected individuals. 31–34 tribute in an autocrine/paracrine manner. Malignant tumors have
Studies of BRCA mutations in canine MGTs have so far been lim- significantly higher tissue concentrations of GH, IGF-1, proges-
ited to tumor gene expression studies and the results have varied; terone, and 17β-estradiol than benign tumors; moreover, levels